Clinical Reviews in Allergy & Immunology (2022) 62:72–89

https://doi.org/10.1007/s12016-020-08830-5

External Environmental Pollution as a Risk Factor for Asthma

Jose Chatkin1   · Liana Correa2 · Ubiratan Santos3

Accepted: 21 December 2020 / Published online: 12 January 2021

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

Abstract
Air pollution is a worrisome risk factor for global morbidity and mortality and plays a special role in many respiratory
conditions. It contributes to around 8 million deaths/year, with outdoor exposure being responsible for more than 4.2
million deaths throughout the world, while more than 3.8 million die from situations related to indoor pollution. Pollutant
agents induce several respiratory symptoms. In addition, there is a clear interference in numerous asthma outcomes, such as
incidence, prevalence, hospital admission, visits to emergency departments, mortality, and asthma attacks, among others.
The particulate matter group of pollutants includes coarse particles/PM10, fine particles/PM2.5, and ultrafine particles/PM0.1.
The gaseous components include ground-level ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide. The timing,
load, and route of allergen exposure are other items affecting allergic disease phenotypes. The complex interaction between
pollutant exposures and human host factors has an implication in the development and rise of asthma as a public health
problem. However, there are hiatuses in the understanding of the pathways in this disease. The routes through which pollutants
induce asthma are multiple, and include the epigenetic changes that occur in the respiratory tract microbiome, oxidative
stress, and immune dysregulation. In addition, the expansion of the modern Westernized lifestyle, which is characterized by
intense urbanization and more time spent indoors, resulted in greater exposure to polluted air. Another point to consider is the
different role of the environment according to age groups. Children growing up in economically disadvantaged neighborhoods
suffer more important negative health impacts. This narrative review highlights the principal polluting agents, their sources
of emission, epidemiological findings, and mechanistic evidence that links environmental exposures to asthma.

Keywords  Air pollution · Particulate matter · Asthma

Introduction lay population [2]. However, air pollution is a major cause of

Air pollution is currently one of the most significant
preventable health risks worldwide. It has been called a
“silent killer” by the World Health Organization (WHO)
[1] because its effects often go unnoticed and are not easily
measured, nor it is associated with health problems by the
* Jose Chatkin
jmchatkin@pucrs.br
1
Pulmonology Division, School of Medicine, Pontifical
Catholic University Rio Grande Do Sul (PUCRS), Hospital
São Lucas da PUCRS, Porto Alegre, Brazil
2
Health Sciences Doctorate Program, School of Medicine,
Pontifical Catholic University Rio Grande Do Sul (PUCRS),
Pulmonologist Hospital São Lucas da PUCRS, Porto Alegre,
Brazil
3
Pulmonology Division of Instituto Do Coração, Hospital das
Clínicas, University of São Paulo Medical School, São Paulo,
Brazil
premature death [3–7]. Another WHO recent alert is about
that 90% of the world’s population breathes inadequate
air—a fact that has not had the expected repercussions [8].
Air pollution is responsible for approximately 4.2 million
deaths in 2015. Air pollution also caused over 100 million
years of life lost, adjusted to the number of years lived
with disability (DALYs) [4]. The European Environmental
Agency (EEA) reported that exposure to particulate matter
and gaseous pollutants above the recommended levels still
remains very common in many countries [2, 5, 9].
External environmental pollution agents are dispersed by
wind currents and do not obey country borders. For example,
polluting agents related to Chinese industrial production
reach Japan and the west coast of the USA. These pollutants
are driven by wind currents [5]. A similar situation takes
place with the smoke resulting from wildfires in the Amazon
rainforest; the air pollutants from these clouds disperse
over long distances [10]. However, the impact of these

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Clinical Reviews in Allergy & Immunology (2022) 62:72–89
burns on mortality and morbidity from acute and chronic
respiratory and cardiovascular outcomes requires more
reliable indicators. Using satellite technology, National
Aeronautics and Space Administration (NASA)-supported
scientists are developing markers to evaluate global air
pollution and the role of the main pollutant agents in some
respiratory diseases, such as asthma. Researchers have
already incorporated some of these indicators in tracking
pollution clouds from wildfires, dust storms, pollens, urban
green space, tropospheric ozone concentrations, particulate
matter, and many others [11, 12].
An evidence accumulated for several decades supports the
idea that air pollution can exacerbate pre-existing asthma.
However, new findings have emerged that suggest air
pollution might also cause new-onset asthma.
There is a relationship between the production of air
pollutants with some habits of the population in certain
regions or countries and with regard to specific professional
situations. An example are the workers’ migration from
workplaces like fields and farms to factories and offices.
Urbanization and economic growth in many countries are
responsible for the increase in some industrial activities and
for the significant increase in motor vehicle emissions. These
factors caused severe air pollution. The westernization of
the way of life of a large part of the world’s population,
with consequent changes in customs, led to the voluntary
isolation of families, whose members stay longer in their
homes or work environments, thereby increasing the impact
of indoor pollution [13–15]. It is accepted that about 80–90%
of the time, urban families stay in indoor environments,
which reinforces the importance of air quality in these
environments [16–18]. In some societies, people spend a
large amount of time indoors with negative consequences
on their health and well-being. Poor indoor air quality can
trigger asthma symptoms, likely related to exposure to
common triggers such as household dust, mold, and tobacco
smoke. Household air quality can be 2 to 5 times worse than
outdoor air quality, and unlike the latter, there are no laws
to regulate it. Indoor air pollution is determined partly by
outdoor air quality depending on ventilation systems and
cleaning practices in residences [5, 13].
There is an interplay of indoor and outdoor environmental
exposures interacting with host factors. The response to
different exposures depends on the individual’s genetic
characteristics. This complex interaction is associated with
the development and progression of allergic diseases, but
the timing, load, and route of allergen exposure also have
an important effect on allergic disease progression and the
severity of symptoms.
Chemical pollution is another form of aggression to the
environment and health. According to Landrigan et  al.,
industries synthesized more than 140,000 new chemical
agents and pesticides in recent years, with significant
73
spread across the planet, and without assessment of possible
deleterious effects before large-scale use [5]. Chemical
exposures associated with occupational asthma, especially
in atopic individuals, include pharmaceuticals, cosmetic
products, flame-retardants, and many others.
There is no reliable control of the several forms of pollution
related to industries, agriculture, and the burning of fossil fuels
by motor vehicles, in both developed and newly industrialized
countries. Unfortunately, air and water pollution, detected
in many countries with extreme poverty and unfavorable
lifestyles, is decreasing very slowly [4, 19–21].
Another worrying aspect related to pollution is the
progressive and severe global warming as a direct threat
to health. Severe heatwaves and climate changes are
associated with increased mortality rates in the elderly and
in individuals with chronic cardiorespiratory diseases. These
climatic phenomena increase exposure to various risk factors
present in the inhaled air, such as pollens, fungi, toxic gases,
and particulate matter.
In a parallel event, outdoor pollution increases
the amount of pollen grains and chemically modified
aeroallergens. Global warming prolongs the vegetation
periods of plants and, if followed by extreme climate events
like heavy precipitation, provokes a sudden release of
massive amounts of allergens. These allergens interact with
sensitized mast cells, inducing the release of inflammatory
mediators and, thereby, leading to severe asthma attacks
[19, 22].
Air pollution is an important component of the exposome
[23], which is the set of environmental exposures throughout
our lives, with a significant negative impact on our health.
The exposome is changing rapidly in recent times due to
modifications in the way we work and live [24, 25]
In contrast to this serious situation, the decrease in
air contamination, with a reduction of the most harmful
components of the exposome, produces substantial, fast,
and favorable results in terms of public health. The control
of these factors has a positive impact on national, regional,
municipal, and even family budgets. This strategic position
reinforces the idea that these risk factors are preventable and
controllable. US reports revealed that investments of around
65 billion dollars starting in the 1970s, aimed at reducing
the impact of pollution, resulted in a budget inflow of 1.5
trillion dollars [5].
External environmental pollution contributes significantly
to asthma and other allergic diseases, chronic rhinosinusitis,
exacerbations of chronic obstructive pulmonary disease
(COPD), respiratory infections, sleep apnea, and several
neoplasms, especially lung cancer. On the other hand, indoor
smoking and pollution caused by cooking using biomass,
kerosene, or diesel derivatives are factors significantly
associated with respiratory health aggression. Although
tobacco use is decreasing in many countries, a considerable
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number of children and adolescents start every day with
traditional forms of tobacco use or with the more recently
introduced variants in Western countries, such as hookah,
electronic cigarettes, and heated tobacco devices. Young
people rapidly accepted these new devices, which represent
a component of pollution that is not yet well known and that
must be better studied [14, 19].
Numerous polluting agents have a clear relationship to
respiratory disease outcomes, especially asthma and COPD.
Among them, PMx, O ­ 3, ­SO2, CO, and N ­ O2 stand out for
inducing cough, sputum, and bronchial hyperresponsiveness
in many patients. In addition, there is an interference in many
outcomes, such as incidence, prevalence, hospital admission,
visits to emergency departments, mortality, and asthma
attacks, among others.
Due to the importance of the binomial respiratory tract/
environmental pollution, this narrative review will focus
on polluting agents related to asthma outcomes [2, 13,
26]. However, this paper will not address the relationship
between asthma and indoor pollution.
Principal Polluting Agents and their Sources
of Emission
Despite the recognition that there is no safe level of pollutants
in the air and that exposure even to concentrations below
the limits recommended by the WHO may pose a risk, there
is still a long way to go towards reducing emissions to an
acceptable level [27]. Many countries have established
parameters that would be safer for one’s health and agree
on the need to update these variables periodically [26].
Measurements over time of the concentrations of some air
pollutants, such as carbon monoxide (CO), nitrogen dioxide
­(NO2), sulfur dioxide (­ SO2), particulate matter (PMx), and
ozone ­(O3), serve as markers of the environmental situation
in a given area [6].
The human body’s responses to air pollutant aggressions
depend on the type, duration, and intensity of exposure,
atmospheric conditions, and individual characteristics.
Socioeconomic aspects of a specific population may at least
partially explain the heterogeneous results detected in a
community, city, or even neighborhood [19].
Primary pollutants are those directly released by the
emission sources. The most relevant are sulfur dioxide
­(SO2), nitrogen oxides (NOx), carbon monoxide (CO), carbon
dioxide ­(CO2), methane (CH4), black carbon (BC), particulate
matter PMx), volatile organic compounds (VOC), and some
metals. Secondary pollutant agents are those formed in the
atmosphere through chemical reactions between primary
pollutants. Examples are hydrogen peroxide (­ H2O2), sulfuric
acid ­(H2SO4), nitric acid (­HNO3), sulfur trioxide (­SO3),
nitrates ­(NO3−), sulfates ­(SO42−), and ozone [13].
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Clinical Reviews in Allergy & Immunology (2022) 62:72–89
The physical-chemical characteristics of these agents are
decisive for the type of aggression that will occur in the
respiratory system. These pollutants may have additive or
synergistic effects with each other, resulting in even more
damage than the isolated effects of each component. More
studies are needed to better clarify these interactions [2].
The main sources of environmental air pollutants are
the results of human action, including automotive vehicles,
ships, airplanes, industries, and the burning of biomass [28].
Table 1 shows the different types of pollutants and how
they damage human tissues [13].
Particulate matter ­(PM10; ­PM2.5; ­PM0.1): This group forms
one of the main aggressors to health and the environment.
The components, suspended in the air, are solid and liquid
particles classified by size. PMx is a mixture of chemicals
(hydrocarbons, salts, and other compounds given off by
vehicles, cooking stoves, and industries) and other natural
components, such as dust and microorganisms. PMs may
cause damage related to its chemical properties, structure,
surface, and composition [13].
Figure 1 illustrates the main air pollutants according to
some physical properties [29].
There are three subgroups: (a) the coarse particles have an
aerodynamic diameter ranging from 2.5 to 10 µm (­ PM10–2.5)
and are usually in the upper airways, while those between 4
and 10 µm ­(MP4–10) are retained in the intermediate regions
of the lower airways. The fine particles have an aerodynamic
diameter of ≤ 2.5 µm ­(PM2.5) and reach the bronchiolar
and alveolar region. The ultrafine particles/UFP have a
diameter smaller than 0.1 µm (­ PM0.1), and pass over the
alveolar barrier to enter the bloodstream, promoting adverse
Table 1  Different types of air pollutants and the damage in human
tissues (adapted from Schraufnagel et al. [13])
Pollutant Injury determinants Tissue affected
Sulfur dioxide ­(SO2) Highly soluble Upper airway
Nitrogen dioxide ­(NO2) Less soluble ­(NO2 and Deeper penetra-
Ozone ­(O3) ­O3) tion; bronchial
Carbon monoxide (CO) and bronchiolar
injury;
Tissue hypoxia
Particulate matter Size, structure, and Large particles:
­(PM10, ­PM2.5, ­PM0.1) composition deter- mucous mem-
mine toxicity branes and upper
airways
Small particles:
bronchioles and
alveoli
Ultrafine particles:
systemic tissue
reactions
PM0.1 particulate matter with an aerodynamic diameter <  0.1 μm,
PM2.5 particulate matter with an aerodynamic diameter <  2.5 μm,
PM10 particulate matter with an aerodynamic diameter < 10 μm
Clinical Reviews in Allergy & Immunology (2022) 62:72–89
Fig. 1  Classification of air pollutants according to some physical
properties (modified from Sompornrattanaphan et al. [29])
effects in various organs. Ultrafine particulate matter carries
harmful adsorbed components to more distal portions of the
lungs [30]. When PM monitors are restricted in terms of
distribution in a specific area, the obtained data might not
be representative of the entire population.
It is worth noting that people with asthma, pneumonia,
diabetes, and respiratory and cardiovascular diseases are
especially susceptible and vulnerable to the effects of
PMx. The particles produce toxic effects according to
their chemical and physical properties. The components
of ­PM10 and ­PM2.5 can be organic (for instance, polycyclic
aromatic hydrocarbons, dioxins, benzene, 1-3 butadiene)
or inorganic (carbon, chlorides, nitrates, sulfates, metals).
­P M 2.5, followed by P ­ M 10, are strongly associated with
diverse respiratory system diseases [31], as their size
permits them to reach interior spaces [8, 32, 33].
The causal relationship between PM chronic exposure
for long years and outcomes of various respiratory diseases
has different pathways, depending on each illness, such as
asthma, rhinitis, COPD, and lung cancer. Transition metals,
polycyclic aromatic hydrocarbons, and environmentally
persistent free radicals are constituents of PM of special
interest because of their potential to cause oxidative stress
and because of the many phenotypic changes associated with
asthma. Additionally, particulate matter frequently contains
various immunogenic substances, such as fungal spores and
pollen, which have been independently associated with the
exacerbation of asthma symptoms.
Particulate matter causes the activation of oxidative
stress through the production of reactive oxygen
75
species, innate immunity, adaptive immunity, and other
mechanisms, leading to the development and exacerbation
of respiratory diseases, as will be discussed in a later
section of this review [2, 13, 34].
The mechanisms involved suggest the development
of persistent oxidative stress and inflammation, which
exacerbate chronic diseases or induce their occurrence.
Acute var iations in environmental pollutant
concentrations are associated with an increase in Emergency
Department visits, hospitalizations, and death rates. PM can
also interact with allergens in the air and induce asthma
exacerbations in previously sensitized people [34].
In summary, substantial evidence supports the idea
that ambient levels of PM exacerbate pre-existing asthma,
particularly by contributing to oxidative stress and allergic
inflammation, and evidence exists in support of PM as a
cause of new cases of asthma.
Table 2 shows the consequences of outdoor pollution
with respect to allergic rhinitis and asthma [22].
Ultrafine particles UFP/PM0.1: The ultrafine particles
(UFP; ­PM0.1) are airborne particulates of <  0.1 μm in
aerodynamic diameter. Typically, UFPs are generated in
the environment, often as secondary products of fossil fuel
combustion, as the results of condensation of semi-volatile
substances, or industrial emissions. Nanoparticles have
similar physical characteristics to UFP, but the difference is in
the production through industrial bioengineering processes.
Urban air contains large quantities of UFPs, such as
components of diesel exhaust particles, products of cooking,
and indoor heating using wood incompletely burned in
poorly ventilated environments.
Figure 2 is a graphical demonstration of the mechanisms
of ­PM0.1-induced lung diseases proposed by Leikauf et al.
[35].
Household pollution is associated with several asthma
risk factors related to incomplete biomass burning used in
domestic cooking without adequate ventilation, as well as
to incense sticks, mosquito repellents, and indoor tobacco
smoke [36].
The extremely small size of UFPs allows them to bypass
host defenses and deposit themselves in the lung, with a high
rate of retention. Thus, for the same volume of air inhaled,
the actual dose and effects of UFPs in the lung might be
significantly greater than that of ­PM2.5.
There is a relationship between ­PM0.1 toxicity with its
smaller size, larger surface area, and material adsorbed
on the surface. These submicron-scale particles have
physicochemical properties that are significantly different
from those of larger PM and, therefore, might exert adverse
health effects, including promoting asthma exacerbation and
allergic sensitization to common allergens.
While the health effects of ­PM10 and ­PM2.5 are based
on their mass, the “weightless’’ nature of UFPs requires a
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Table 2  Consequences of outdoor air pollution over allergic rhinitis and asthma (adapted from Eguiluz-Gracia et al. [22])
Environmental factors
Pollution from traffic and industry ­(PM10, ­PM2.5, NO, ­NO2)
During childhood
During adulthood
Lifelong
Livestock farming (organic dust, toxins form microorganisms, gases like
ammonia and methane)
Black carbon
Interaction between air pollutants ­(PM10, nitrogen oxides) and allergens (pollen, fungal spores)
Production of more pollen, more allergens per pollen grain, and more PALMs Potentially, facilitation of IgE sensitization against aeroallergens
per pollen grain
different metric for exposure, such as the particle number
and surface area, as shown in Table 3 [30].
Short-term UFP exposure causes various respiratory
symptoms, such as coughing and dyspnoea, but also the
worsening of spirometric parameters, the greater use of
medications to control asthma, and a higher frequency of
hospitalizations for asthma. Higher frequency of medical
visits for respiratory diseases is also associated with
increased levels of P
­ M0.1 [37, 38]. In comparison to P
­ M2.5,
UFPs probably cause greater lung inflammation and remain
longer in the lungs. Schraufnagel reported that decreased
peak expiratory flow and increased respiratory symptoms in
Fig. 2  The proposed mechanisms of ultrafine particles induced lung
diseases (adapted from Leikauf et al. [35])
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Clinical Reviews in Allergy & Immunology (2022) 62:72–89
Health outcomes
Higher asthma prevalence after the school age
Possibly higher asthma prevalence
Poorer lung function
Higher rate of asthma exacerbations
Conflicting results on AR onset
Decreased lung function
Possibly epigenetic changes leading to increased type two
inflammation in children
Higher rate of asthma-related hospitalizations
asthmatic subjects were associated with exposure to ambient
fine and ultrafine particles. However, the effects of the 5-day
UFP mean number were larger than that expected by the fine
particles, and its effect on peak expiratory flow, FEV1, and
forced vital capacity was more intense than that of ­PM10
[30].
Cereceda-Balic et al. [38] showed that the largest increase in
the OR for pediatric asthma-related visits was associated with
the 4-day mean concentration of UFPs, while the concentration
rises of PM, black carbon, and sulfur reported were lower [39].
However, many findings are still controversial.
Weichenthal et al., assessing more than 1 million adults,
did not find any association between ­P M0.1 exposure for
long periods, with clinical manifestations, after adjusting
for ­P M 2.5 and N­ O 2 [40]. From this same perspective,
Clifford et al. stated that the number of ultrafine particles
did not show independent association with respiratory
symptoms, asthma diagnosis, or changes in lung function
[41].
In most of these situations, oxidant injury plays an
important role in UFP-induced adverse health effects,
including exacerbation and promotion of asthma
and chronic obstr uctive pulmonary disease. The
inf lammatory properties of ­P M 0.1 and its ability to
produce ROS explain these exacerbations, leading to
the production of pro-inflammatory cytokines and more
airway inflammation.
It is unknown how long UFP persists in human airways
and how long a potential pro-allergic effect continues to
exist. Schauman et al. observed no significant effects of
UFP on allergic inflammation at 24 h after an allergen
exposure challenge compared with exposure with filtered
air. However, the authors speculate that inhaled UFP
particles in real life might have a long-term effect on the
inflammatory course in asthmatic patients [42].
Clinical Reviews in Allergy & Immunology (2022) 62:72–89 77

Table 3  Comparison of ­PM10, Characteristics PM10 PM2.5 UFP

­PM2.5, and UFP (adapted from
Schraufnagel [30]) Aerodynamic diameter (mm) 2.5–10 2.5–0.1 < 0.1
Deposition in alveolar space No No Yes
Surface area/mass ratio + ++ +++
Organic carbon content + ++ +++
Elemental carbon content +++ ++ +
Metal content +++ ++ +
Exposure metrics Mass Mass Particle num-
ber or surface
area
Central monitoring sites Yes Yes None
National Ambient Air Quality Stand- 150 mg/m3 (24 h) 35 mg/m3 (24 h) None
ards (NAAQS)/US EPA

The potential for P ­ M0.1 to cause harm to health is great,
but their precise role in many illnesses is still unknown.
Gaseous Components ­(NO2, ­SO2, ­O3, CO)
Nitrogen dioxide (­NO2): Cooking food with indoor gas
stoves releases high ­NO2 concentrations compared with
findings in the outdoor environment.
Immediately after inhalation, ­NO 2 dissolves at the
most distal airways and at the alveoli. The next step is the
production of reactive oxygen and nitrogen substances
(ROS and NOS). These substances induce oxidative stress,
damaging the respiratory tract, especially in asthmatics.
An increase in respiratory symptoms such as wheezing,
dyspnea, and chest tightness might start with very low N ­ O2
exposure [34, 43]. This gas attaches to hemoglobin and other
iron-containing proteins, but only if its contact point is in a
short distance [13].
Considering that ­NO2 is one of the major components
of TRAP (traffic-related air pollution), such emissions
should be mitigated and included in public health asthma
control programs. Meta-analyses detected an association
between TRAP exposure and pediatric asthma incidence,
indicating an association with N ­ O 2, but results were
mixed for associations with ­PM2.5. The US Environmental
Protection Agency and Health Canada pointed out the causal
relationship between long-term ­NO2 exposure and pediatric
asthma [44, 45].
NO2 is a potent irritant of the respiratory system, as it
penetrates deep in the lung, inducing respiratory diseases,
coughing, wheezing, dyspnea, bronchospasm, and even
pulmonary edema when inhaled at high concentrations.
It seems that concentrations over 0.2 ppm produce these
adverse effects in humans, while concentrations higher than
2.0 ppm affect T lymphocytes, particularly the CD8+ cells
and NK cells that produce the human immune response.
Long-term exposure to high levels of ­NO2 can be responsible
for chronic lung disease [8].
Sulfur dioxide ­(SO2): The outdoor release of this gas
occurs through the combustion of fossil material, as in
automotive vehicles, ships, airplanes, and industrial plants,
and through release into the atmosphere by volcanoes.
Sulfur dioxide is one of the main sources of acid rain, whose
aerosols have pH < 1.0.
The major health problems associated with ­SO2 emissions
in industrialized areas are respiratory symptoms, bronchitis,
and mucus production. As it is a sensory irritant and
penetrates deep into the lung, this gas interacts with sensory
receptors, causing bronchoconstriction.
SO2 is highly soluble in water and largely damages
the upper airways and skin. Its effects on the respiratory
tract may be short-term, such as respiratory symptoms
and increased frequency of emergency room visits and
hospitalizations related to respiratory conditions. Long-term
exposure causes a decrease in lung function [26, 46–51].
Ozone ­(O3): ­O3 is a compound of low water-solubility
that reaches the more distal regions of the lungs, achieving
the alveolar level. Although ozone in the stratosphere plays a
protective role against ultraviolet irradiation, it is harmful in
high concentrations at ground level, affecting the respiratory
and cardiovascular system [52].
Toxic effects induced by ozone occur in urban areas
all over the world, causing biochemical, morphologic,
functional, and immunological disorders [53].
Asthmatic individuals probably have a greater
susceptibility to the effects of O­ 3 leading to more severe
asthma due to an increase in bronchial contractility and
an action in the inflammatory cascade [54]. The main
consequences of ozone’s inhalation are the increased
frequency of asthma exacerbations, the need for more
bronchodilator medications, and an increased number
of visits to emergency services, even in low external
environmental concentrations of ozone. There is a decrease

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in FEV1 and greater responsiveness during periods of high
atmospheric ­O3 concentrations [43, 55].
Li X et al. recently demonstrated that the better interval for
evaluating ozone’s effect on asthma exacerbations is within
eight hours of exposure. When assessed using the daily mean
concentration, this association does not remain significant [53].
CO: Carbon monoxide is a highly soluble and nonirritating
gas that readily passes into the bloodstream. Its toxicity results
mainly from its successful competing with oxygen in binding to
hemoglobin, which results in tissue hypoxia [13].
Evidence of the acute effects of ambient CO pollution on
morbidity risk in developing countries is scarce and inconsistent.
Even in the same country, such as China, differing health outcomes,
sample sizes, and characteristics of study locations may explain
the contradictory result. Liu H et al. detected 916,388 admissions
during January 2014 to December 2015. A 1-mg/m3 increase in
CO concentrations corresponded to a 4.44% (95% CI, 3.97–4.92%)
increase in respiratory admissions on the same day [56]. The
associations remained significant after controlling for criteria
co-pollutants ­(PM2.5, ­PM10, ­NO2, ­SO2, and O ­ 3). Associations
between CO and daily hospital admission for respiratory diseases
appeared to be stronger in females and the elderly. The authors
speculate that the sex differences in the magnitude of effect may be
attributable to hormones and structural/morphological differences
in the respiratory system between males and females. Changes in
the structure of the respiratory system with advanced age and
declining biological function and anti-infection ability may explain
the higher effect estimates in the elderly.
The incomplete combustion of fossil fuel produces CO and
­CO2. Higher amounts of ­CO2 in the atmosphere increase the
duration of pollen seasons, the quantity of pollen produced
by plants, and, possibly, the allergenic potential of the pollen.
This chain of events has a relationship to stronger IgE binding
intensity. The consequence is an increased rate of allergic asthma
attacks [57].
Evidence suggests an association between exposure to CO
and moderate or severe asthma exacerbations only in adults
(OR1.045, 1.005–1.086). Although it was not confirmed in chil-
dren, during asthma attacks in infants and toddlers, Ohara et al.
detected that their exhaled CO levels were significantly higher
than those of subjects with asymptomatic asthma (P < 0.0001)
and healthy children (P < 0.0001) [57].
Another point to be highlighted is that significant association
was observed between decreasing asthma death rates with lower
CO levels [46].
Toxic heavy metals: Heavy metals such as lead, arsenic,
and cadmium induce local inflammation in the airways and,
potentially, systemic effects. In the lungs, they determinate the
depletion of antioxidants, and, as a consequence, induce oxidative
stress, and an increase in pro-inflammatory agent content [58].
Recently, Koh et  al. detected a significant association
between heavy metals with asthma, allergic rhinitis, and airflow
obstruction, pointing especially at the health consequences of
lead, cadmium, and mercury [33].
Epidemiological Findings
Pollution is a real public health problem in both pediatric
and adult populations. Outdoor pollution exposure is the fifth
leading risk factor for deaths in the world, accounting for 4.2
million deaths, while more than 3.8 million die from situations
related to indoor pollution. Considering just the asthma deaths
in 2016, the Global Burden of Disease estimated that 420,000
people in the world died from asthma, more than 1000 per
day [13]. Worldwide, asthma was the second leading cause of
death among chronic respiratory diseases, with a death rate of
6.48/100,000 (4.43–8.39). The Global Asthma Report 2018
informs that the proportion of asthma deaths in all-causes
mortality was 0.88% (0.60–1.14) [59].
Table 4 shows the chronic respiratory disease-attributable
death rates and DALY rates per 100,000 individuals [60].
However, as compared with other chronic respiratory
diseases, asthma mortality is not frequent. It is usually attributed
to several risk factors, but the majority are preventable and
related to the bad management of asthma [61, 62].
The asthma mortality rate, evaluated in 46 countries,
decreased from 0.44 deaths/100,000 (0.39–0.48) in 1993
to 0.19/100,000 (0.18–0.21) in 2006, though without a

Table 4  Chronic respiratory disease-attributable death rates and DALY rates per 100,000 individuals (adapted from Soriano et al. [60])
Death rate/100,000 Proportion all-cause deaths DALY rate/100,000 Proportion all-
cause DALYS %

All chronic respirat diseases 51.23 (49.61–52.94) 7.00% (6.76–7.23) 1470.03 (1369.68–1566.56) 4.50% (4.20–4.78)
COPD 41.85 (39.64–43.96) 5.72% (5.43–5.97) 1068.02 (994.47–1135.50) 3.27% (2.96–3.56)
Asthma 6.48 (4.43–8.39) 0.88% (0.60–1.14) 297.92 (236.69–370-88) 0.91% (0.76–1.09)
Interstitial lung diseases and pulmo- 1.93 (1.50–2.37) 0.26% (0.20–0.32) 44.04 (36.19–53.43) 0.13% (0.11–0.16)
nary sarcoidosis
Pneumoconiosis 0.28 (0.27–0.30) 0.04% (0.04–0.04) 6,64 (6.18–7.17) 0.02% (0.02–0.02)
Other chronic respiratory diseases 0.68 (0.60–0.78) 0.09% (0.08–0.11) 53.40 (47.16–59.63) 0.16% (0.05–0.18)

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Clinical Reviews in Allergy & Immunology (2022) 62:72–89
significant difference in the following period, 2006–2012
[61].
Air pollution plays a role in asthma mortality. Liu Y
et al. included 4454 cases of asthma deaths during the
study period (2013–2018), with an average of at least two
asthma death cases per day. The authors found an 11%
increase in asthma deaths related to an increase of N ­ O2
concentration over the 3  days before death occurred.
They also reported that following increases in exposures
to ­PM2.5 and ­O3, the OR for asthma mortality increased
by 7% and 9%, respectively. This report concludes that an
association exists between asthma deaths and short-term
air pollution exposure [31].
In a meta-analysis, Veremchuk et al., studying an urban
population, reported that an association between asthma
morbidity and air pollution was stronger in children than
in adolescents and adults [63].
The role that environmental pollution plays in the
various asthma outcomes is becoming clearer, not only
in mortality but also in hospitalizations, Emergency
Department visits, exacerbations, and others, with the
advance of the understanding of the deleterious effects
of the polluting agents. The Asthma Global Burden
Report estimated that asthma-related emergency room
visits occurred between 9–23 million and 5–10 million
of attributable to ozone and P ­ M 2.5, respectively. Those
rates represented 8–20% and 4–9% of the annual number
of global visits, respectively [64].
The prevalence of asthma is increasing worldwide,
especially in densely industrialized urban regions. Cross-
sectional and longitudinal studies show the association
between asthma and exposure to air pollutants [46,
65]. Previously, in 2006, Watts had already described
physicians’ concern about the great increase in asthma
incidence in China after the industrial development of the
last decades, likely associated with a significant increase
in the concentration of pollutants [66].
Numerous polluting agents exacerbate respiratory
diseases, especially asthma and COPD. Among them, PMs,
­O3, ­SO2, CO, and ­NO2 drew attention and were associated
with respiratory symptoms such as cough, sputum, and
bronchial hyper-responsiveness. Even short-term exposures
to high concentrations of environmental pollutants are
associated with reduced lung function, exacerbations of
asthma, and higher frequencies of visits to emergency
departments, hospitalizations, and deaths [64].
Pediatric Asthma
It is generally difficult to quantify the effects of an individual
pollutant and respiratory diseases without multi-pollutant
models. This difficulty might explain some inconsistent
findings between ambient pollutants and respiratory diseases.
79
Dong et al. published a study in 2011 evaluating 30,139
Chinese children aged 3 to 12  years, stratified by their
allergic predisposition. The results showed that allergic
children were more susceptible to air pollutants than the
control group, and that this was more frequent among
females. They also detected a strong correlation between
­PM10 and S ­ O2 (r = 0.78), ­PM10 and N ­ O2 (r = 0.70), ­PM10
and ­O3 (r = 0.74), ­SO2 and ­O3 (r = 0.67), and ­NO2 and ­O3
(r = 0.66). These findings prove that it is difficult to distin-
guish the effects of individual air pollutants [67].
Achakulwisut et al. [68] studied the annual burden of
pediatric asthma incidence attributable to ambient N ­ O2
pollution, evaluating the intra-urban and near-roadway
exposure in 125 major cities of 194 countries. Their findings
suggested that a substantial portion of pediatric asthma
incidence could be avoided by reducing ­NO2 pollution in
both developed and developing countries, especially in urban
areas. Anenberg et al. also mentioned the importance of ­NO2
in asthma as a public health problem [64].
In a recent large study, Lee et al. detailed 28,824 asthma
exacerbations that required hospital admission and the
lag period after exposure. They evaluated air pollutants,
weather, aeroallergens, respiratory viral infections, and the
effect in five age groups (infants, preschool children, school-
aged children, adults, and the elderly). The conclusion was
that asthma exacerbations were associated with O ­ 3, daily
temperature range, and tree pollen on lag day 0; with ­PM10,
­NO2, CO, and influenza virus infection on lag day 3; and
with ­SO2 and weed pollen on lag day 5 [69].
Zhao Y et al. studied during the period January 2013 to
August 2017 the data records of 89,484 hospital outpatient
visits for respiratory diseases. They found that a short-term
exposure to ambient CO was associated with an increased
risk of outpatient visits for respiratory diseases. In asthma,
an increase in ambient CO corresponded to an increased
risk in outpatient visits for asthma of 8.86% (95% CI 4.89%,
12.98%) [70].
A study conducted with children in Athens, Greece,
aimed to assess the effects of acute exposure to air pollut-
ants, revealed that an increase of 10 μg/m3 in ­MP10 and ­SO2
levels was associated with the increments of 2.2% (95%
CI 0.1–5, 1) and 6.0% (95% CI 0.9–11.3), respectively, for
asthma in emergency services [71].
Another publication on children and adolescents up to
18 years old described a higher frequency of hospitalizations
for asthma associated with increases in NOx concentrations
(OR 1.11; 95% CI: 1.05–1.17), N ­ O2 (OR1.10; 1.04–1.16),
­MP10 (OR 1.07; 1.03–1.12), and ­MP2.5 (OR 1.09; 1.04–1.13)
[72].
In Araraquara, Brazil, a city located in the sugarcane
crop region, hospitalizations for asthma increased with
the augmentation of pollutant levels. During the straw
burning period, hospital admissions for asthma, at all ages,
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80
were around 50% higher. An increment of 10 μg/m3 in the
concentration of total suspended particles was associated
with an increase of 11.6% (5.4–17.7) in hospital admissions
for asthma [51]. Another study carried out in Brazil found
that after a period of forest burning, when the concentrations
of ­MP2.5 reached values of up to 400 µg/m3, there was a
100% increase in emergency care for children under 10 years
of age due to respiratory diseases, including asthma [73].
Pollution seems to be related to worse outcomes not only
for patients with a previously confirmed asthma diagnosis
but also for the emergence of new cases, that is, an increase
in the incidence of the disease. Growing evidence confirms
that inhalation of pollutants in childhood is associated with
an increased risk of developing asthma and impairment of
the development of normal lung function [52, 74–76].
Several reports show increases in the frequency of new
cases of asthma in childhood associated with continued
exposure to pollutants generated by the burning of fossil
fuels, such as black carbon, ­PM2.5, and ­NO2 [54, 55, 77].
In a comprehensive assessment of the respiratory
consequences of forest fires in San Diego, USA, in 2007,
there were 21,353 hospitalizations, 25,922 emergency visits,
and 297,698 outpatient consultations. There was a 34%
increase in all respiratory diagnoses, but asthma increased
by 112%. Among children under 4 years old and those up to 1
year old, Emergency Department visits for asthma increased
70% and 243%, respectively. An increase in the concentration
of 10 μg/m3 of P­ M2.5 had, as a consequence, OR of 1.08 (95%
CI 1.04–1.13) for emergency care for asthma [78].
The Southern California Children Health Study (CHS),
conducted in 12 communities in California, USA, with different
levels of ozone concentration, included 3535 students with no
previous history of asthma. The researchers followed these
volunteers for 5 years and found that 265 children developed
asthma. In communities with higher ozone concentrations, the
OR for asthma development among children who practiced
outdoor sports three or more days per week was 3.3 (95% CI
1.9–5.8) times greater than that of children who did not play
sports. In areas with low ­O3 concentrations, outdoor sport
practice was not a significant risk factor for asthma appearance.
The same type of result was previously observed considering
the length of stay in external environments; only permanence
in areas with a high concentration of ­O3 was directly associated
with new cases of asthma [52].
In the Netherlands, a study following 3863 children for 8
years reported an increase in the prevalence and incidence
of asthma of 28% and 26%, respectively; this was associated
with exposure of vehicular origin, especially with increasing
concentrations of ­MP2.5 [79].
To assess a possible relationship between asthma
incidence rates with pollution, a study evaluated the
emergence of new cases in people up to 18 years of age in
48 US states and the District of Columbia, in two waves
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(2000 and 2010). The authors estimated that the number of
asthma cases attributed to vehicular pollution ranged from
209,100 to 331,200 in 2000, falling to 141,900 to 286,500 in
2010. The possible cause of such a drop was the significant
reduction in N ­ O2 and PM concentrations, evidencing not
only the association of exposure to the disease but also the
benefits of reducing pollutants [80].
Another study, with similar objectives, reported data from
194 countries. The authors estimated that in 2015 four million
new cases of asthma in individuals aged 18 years or less were
related to exposure to ­NO2. That number represented about
13% of the global annual asthma incidence [68].
There was previous evidence that the ­MP10 fraction could
be more harmful to the airway epithelium than ­PM2.5, possibly
related to the iron content of these larger particles. In animal
models, Herbert et al. [81] demonstrated a clear cause-and-
effect relationship between rates of ­PM10 in ambient air and
allergic asthma, for both asthma induction and exacerbation.
However, another study detected a different result, that is,
greater evidence of the effect of ­PM2.5 concentrations [82].
Probably, the variation in particle composition between
studies is the main reason for such different findings.
The effect of urbanization on the increase of the
frequency of new asthma cases, demonstrated in cross-
sectional studies and longitudinal studies, strengthened the
hypothesis of the direct interference in the immune system
and, consequently, in the prevalence of asthma [83]. After
one moves to an urban area, daily habits usually change, with
families spending more time indoors, especially at home or
offices. The World Health Organization reports that in urban
settings, individuals can spend up to 90% of their time in
household environments. In addition, data show that such
domestic environments are two to five times more polluted
than outdoor areas [1].
Cross-sectional studies show that when inhabitants
of rural areas acquire urban lifestyles or move to more
densely populated centers, there is an increased frequency
of wheezing patients, probably related to their breathing
more polluted air. In addition, several longitudinal studies
specifically analyzed the phenomenon of urbanization
through air pollution related to urban traffic and found
an association with increased incidence, prevalence, and
exacerbation of asthma in children and adults [83–88].
In 2013, the study Improving Knowledge and
Communication for Decision Making on Air Pollution and
Health in Europe (APHEKOM), assessing the impact of
children living close to high-traffic routes in 10 European
cities, revealed that air pollution was responsible for
up to 14% of all asthma patients and for 15% of asthma
exacerbations [86].
It is now clearer that TRAP plays a special role in air
pollution and health aggression. The smoke from burning
diesel oil (diesel exhaust particles) contributes up to 90%
Clinical Reviews in Allergy & Immunology (2022) 62:72–89
of the PMs that constitute TRAP. These components induce
oxidative stress and bronchial hyperresponsiveness, as
well as increase allergic responses and inflammation in the
airways. In addition, TRAP is associated with reduced lung
growth and asthma [75, 75].
The ESCAPE study evaluated five cohorts of newborns in
several countries in Europe, aiming to study the association
between TRAP exposure and childhood asthma or wheezing.
The authors initially did not detect a significant association
between PM and NOx with the prevalence of asthma
or current wheezing in childhood [75]. However, a data
reanalysis, which resulted in several publications, found that
exposure to those pollutants was associated with worse lung
function in children aged 14 to 16 years. In addition, also
described was the relationship between exposure to ­PM2.5
and ­NO2 with a higher incidence of asthma. The OR for
asthma incidence were 1.29 (95% CI 1.00–1.66) and 1.13
(95% CI 1.02–1.25), respectively [75, 89, 90].
Evidence suggests that 13% of the global incidence of
asthma in children could be attributable to TRAP and data
showed that air pollution has a negative impact on asthma
outcomes in both adult and pediatric populations. The
Global Initiative for Asthma (GINA) includes this issue in
the 2020 update [59, 91].
Khreis et al., in a systematic review and meta-analysis of
41 studies, showed a significant effect of exposure to black
carbon (BC), ­NO2, ­PM2.5, and ­PM10 on the risk of developing
asthma in children under 18 [84]. After that publication,
several papers demonstrated that a high concentration of N­ O2
and BC in urban areas showed the important relationship of
heavy traffic with higher prevalence and incidence of asthma
in children [80, 88, 92–94].
Exposure to N ­ O2 and NOx derived from urban traffic is
responsible, yearly, to 7% and 12% of new asthma cases,
respectively. Exposure to these pollutants from industries,
heating equipment, aviation, and several others added to
TRAP composition increase the proportion to 22% and 35%,
respectively [93].
The same group of researchers confirmed that the TRAP-
related pollutants P ­ M2.5, ­PM10, and BC play a partial role
in 7%, 11%, and 12% of the annual incidences of childhood
asthma, respectively [80]. The percentages related to these
same pollutants, considering all other sources, would be
27%, 33%, and 15%, respectively [76].
The longitudinal assessment of the incidence of asthma
in childhood allows for the evaluating of the number of
preventable cases if the levels of the pollutants were in
accordance with WHO recommendations, as suggested
by a nationwide study carried out in the USA (80). In
the same year, Khreis et al. [76] assessed the association
between air pollution and the emergence of new cases of
asthma in more than 63 million children in 18 European
countries. They reported the possible prevention of
81
emergence per year of 2,434 and 66,567 new cases of
asthma if the levels of ­N O 2 and ­P M 2.5 , respectively,
in those countries were within the standards set for
air quality by WHO [1, 26, 27, 95]. If those European
countries obeyed the suggested limits for black carbon,
in addition to N
­ O2 and ­PM2.5, the annual decrease would
be 135,257 (23%), 191,883 (33%), and 89,191 (15%)
cases, respectively. The authors pointed out that the WHO
parameters should be outdated and suggest that such a
correction probably would describe a more realistic
asthma burden incidence.
Table 5 shows the effects of outdoor air pollutants on
asthma if legal concentrations are exceeded [96].
Confounding factors, such as socioeconomic status,
smoking, and family atopy, may interfere with the assessment
of the emergence of new cases of childhood asthma.
Unfortunately, many studies did not control those variables.
Adult Asthma
Studies about the associations between outdoor air pollu-
tion and asthma in adults are not as common as they are in
children, and the underlying biological mechanisms are not
completely understood [47, 97, 98].
When the exposure is later, in adulthood, the conclusions
are less definitive, although some studies suggested that
an association of new cases of asthma with such exposure
might become a risk factor for accelerated decline in adult
spirometric values [99–101].
Kunzli et  al., in one of the first studies looking for
an association between adult asthma and air pollution,
evaluated 2725 nonsmoking individuals aged between 18
and 60 years old. The results showed that residents in more
polluted areas had a higher risk of developing asthma,
around 30% for each increase of 1  μg/m 3 in the ­M P 10
concentration [92].
More recently, Koh Y et al. [33] reported the results of
a study with adults (> 19 year old) assessing the Korean
database population looking for data on heavy metal serum
levels. The authors assessed 16,809 adults with asthma and
atopic dermatitis, 9547 with allergic rhinitis and allergic
multimorbidities, and 8092 with complete pulmonary
function testing. Their results indicated that serum lead
level was associated with self-reported asthma (aOR 1.10;
1.02–1.17) and atopic dermatitis (aOR 1.12; 1.02–1.23),
cadmium level was associated with self-reported asthma
(aOR1.36; 1.19–1.55) and allergic rhinitis (aOR 1.11;
1.03–1.19), and mercury level was not associated with any
of the studied allergic conditions.
In a study with 650,000 participants from three
European cohorts, Cai et al. [94] reported the relationship
between pollution and the prevalence of asthma in
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Table 5  Effects of outdoor air Pollutant Concentration (µg/m3)
pollutants on asthma outcomes
if legal concentrations are
exceeded (adapted from Tiotiu O3 100 (8-h mean)
et al. [96])
NO2 200 (1-h mean)
CO 30 (1-h mean)
SO2 20 (24-h mean)
PM2.5 10 (annual mean)
25 (24-h mean)
PM10 10 (annual mean)
50 (24-h mean)
adults. They found that prolonged exposure to P ­ M10 was
associated with an increase of 12.8% in the prevalence
of asthma.
Orellano et al., in a meta-analysis design, considered the
most important outdoor air pollutants to be PM, ­O3, ­SO2,
­NO2, CO, and Lead (Pb), with a significant association
between several of those pollutants and gases with moderate
or severe exacerbations of asthma [46].
Bowatte G et  al. investigated the associations between
nitrogen dioxide (­NO2) exposure, traffic road, and persistent
asthma, following the patients over eight years. Living close to a
major road was a risk factor for the development and persistence
of asthma in adults. For those who never had asthma by age
45, living < 200 m from a major road presented increased
odds of new and persistent asthma (aOR 5.20; 95% CI: 1.07,
25.4). Asthmatic participants at 45 also had an increased risk
of persistent asthma up to 53 years if they lived < 200 m from a
major road, compared with asthmatic participants living > 200 m
from a major road (aOR 5.21; 95% CI 1.54, 17.6) [102].
Havet et  al. found increases in adult plasma levels of
fluorescent oxidation products (FLOPs) after ­O3 and ­PM10
exposures and that this increase was associated with a risk for
persistent asthma. These findings strengthen the role that FLOP
levels play in inducing oxidative stress [103]. These findings are
in accordance with previous studies of uncontrolled asthma [98],
current asthma [97], and severe asthma in adults [104].
Recent papers addressed various aspects of asthma in adults
and exposure to polluting agents. Liu Y et al. found that short-
term exposures to P­ M2.5, ­NO2, and O
­ 3 probably increase the risk
of adult asthma mortality [31]. Scibor et al. reported, in 2020,
an association between exposures to P ­ M10 and worse quality of
life in adult asthma patients [105].
Improvement in Air Quality and the Impact
on Asthma Cases
Several studies noted the relationship between the reduction
of external environmental pollution and the improvement
of respiratory conditions. Evidence of improvements in air
13
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Asthma symp- Exacerba- Hospitaliza- Lung function
toms tions tions
- ↑ ↑ ↓
↑ ↑ ↑ ↓
- ↑ -
↑ ↑ ↑ ↓
↑ ↑ ↑ ↓
↑ ↑ ↑ ↓
quality concomitant with a decrease in asthma cases occurs
in the short term and long term.
Garcia et al. [106] reported that the improvement in air
quality in Southern California between 1993 and 2014 was
associated with a lower incidence of childhood asthma, a
conclusion that remained even after controlling for several
possible confounding factors. The study included 4,140
children, with no previous history of asthma. The researchers
identified 525 new cases of asthma and found, in the
respective communities of each case, a progressive decrease
in the levels of pollution measured in three assessments
throughout the study. The relative risk for reducing the
incidence of asthma was 0.83 cases/100 persons/year
for each decrease of 4.3 ppb of N ­ O2, and 1.53 cases/100
persons/year for each decrease of 8.1 μg/m3 of P ­ M2.5. These
results pointed to a reduction in the incidence of asthma
by about 20% in the region during the studied period. The
results of this and other studies indicate the possible benefits
of reducing the concentrations of polluting agents to values
below the maximum limits adopted.
A very impressive result was obtained through a major
effort during the 1996 Olympic Games in Atlanta, USA, to
reduce urban pollution. During the period of the Games, traffic
was prevented from circulating in various areas of the city,
with a measured decrease of around 22%. This administrative
action was followed by a drop in the daily peak of the levels
of ­O3 (− 28%), ­NO2 (− 7%), CO (− 19%), and ­MP10 (− 16%)
compared with the previous 3 weeks and after the games. In
this period, there was a 40% reduction in medical visits among
asthmatic children and an 11–19% decline in asthma care at
all ages in emergency services [107].
Likewise, during the 2008 Beijing Olympic Games, there
was a drop in concentrations of M ­ P2.5 and O
­ 3 from 78.8 μg/
m3 to 46.7 μg/m3 and from 65.8 to 61 ppb, respectively,
as well as a 41.6% decrease in asthma care in emergency
services [108].
NASA pollution-monitoring satellites and the European
Space Agency detected significant decreases in ­NO2 levels
across China compared with before and during the pandemic
quarantine. The reduction of ­NO2 pollution was visible first
near Wuhan; eventually, N ­ O2 dropped across China and
Clinical Reviews in Allergy & Immunology (2022) 62:72–89
around the world. The concentrations of nitrogen dioxide
were 10–30% lower than in comparable periods in 2019.
The European Environment Agency found a similarly large
drop in air pollution across European cities, such as a ­NO2
decrease of 47% in Bergamo, Italy and 55% in Barcelona,
Spain, as compared with the same period in 2019.
Berman and Ebisu evaluated the impact of the COVID-19
pandemic on measured USA air pollution using the federal
air-monitoring network. They detected a sharp decrease
in ­NO2 levels (25.5% reduction with absolute reductions
4.8 ppb). The ­PM2.5 reduction was significant (0.7 μg/m3
or 11.3%) when examining counties that instituted early
non-essential business closures, while rural counties did
not indicate any statistically significant difference between
current and historical data [109].
A decrease of 6% in global pollution followed the
reduction of global activities due to the coronavirus
pandemic. However, the impact of such a reduction in asthma
and COPD patients is just beginning to be evaluated [110].
Main Pathophysiological Pathways
Different responses to exposure to the same polluting agents
are related to several intrinsic factors of each subject and
extrinsic factors. The intrinsic factors most frequently
studied are age, sex, pre-existing diseases, diet, obesity, and
viral infections. The genetic load has a crucial role. The
polymorphisms recognized in the control of oxidative stress
are NQO1, GSTM1, and GSTP1, while the TNF has a role
in inflammatory mechanisms.
However, extrinsic factors, such as climate and
environment changes, individual socioeconomic restrictions,
income differences among countries, cities, or areas, and
nutritional status, play a significant role [22, 69, 111].
Ozone, ­NO2, and ­PM2.5 are the pollutant agents related
to airway inflammation, while ozone and nitrogen dioxide
produce airway hyperresponsiveness. In addition, oxidative
stress has been associated with ozone, N ­ O2, and PM2 [5].
Through several pathways, these pollutants are associated
with exacerbations, mortality, and even the onset of asthma.
Gowers et  al. [77] described several mechanisms to
explain the role of outdoor pollution in the induction of
asthma. Among them, the authors identified airway damage
and remodeling through oxidative stress plus inflammatory
pathways and immunological responses. In addition, they
also considered the enhancement of respiratory sensitization
to aeroallergens decreasing the airway hyperreactivity
threshold. There is an intense interconnection among these
mechanisms [28], as schematically shown in Fig. 3.
A basal mechanism leading to the development of several
lung diseases associated with air pollutants is the structural
rearrangement of the airway epithelium, extracellular matrix,
83
smooth muscle, and cells involved with immune responses
leading to the inflammatory process. The local inflammation
occurs with infiltrations of neutrophils and macrophages.
These cells start to secrete pro-inflammatory cytokines, such
as tumor necrosis factor-alpha (TNFα) and interleukins 6
(IL6) and 8 (IL8). TNFα and interferon-gamma (INFγ)
increase nitric oxide synthesis, which is another source of
free oxygen radicals.
Free radicals and lung inflammation represent a response
against the pollutant agents. However, when there is a large
production of reactive oxygen and nitrogen species (ROS
and NOS), it becomes an adverse effect [112]. Recent studies
suggest the environmentally persistent free radicals (EPFR)
as another important component that can last in the ambient
up to 21 days [113].
This chain of events results in an inflammatory state
responsible for exacerbations or worsening in asthmatic
patients when exposed to pollutant agents [114]. Animal
studies, such as the exposure of rats to ozone, in environments
without allergens, induce type 2 immunological reactions, as
a non-allergic asthma response. These responses are not the
classic type 1 reactions, usually involved in allergic rhinitis
and asthma, and amplify the understanding of the relationship
between pollution and asthma [88].
Patients with severe asthma produce greater amounts of
cytokines when exposed to PMs and diesel exhaustion as
compared with healthy individuals or non-severe asthma
phenotypes [22].
The reduced function of Treg lymphocytes and increased
IgE levels is another point in the complex relationship
between air pollution and atopic diseases. A different
mechanism plays a central role in non-atopic asthma, which
is an increment of CD4 and CD8 T lymphocyte production
in response to antigens in polluted environments [28, 115].
Infections by adenovirus and other pathogens can also
interact with oxidative stress and pollutant particles, thus
inducing disease exacerbation in patients with chronic
respiratory disease. This is especially important when
considering the role that ultrafine particles play in asthma.
UFP is known to act as a carrier of microorganisms to deep
regions of the lungs [116].
In addition, air pollution interacts with plants and
fungi, promoting an increase in the production of pollens
and their respective allergenic capacity. For example, in
areas with a high concentration of C ­ O2, ragweed grows
faster, f lourishes earlier, and, thus, produces more
pollen than ragweed in clean-air rural areas. A prick
test performed with extracts obtained from pollens in
polluted areas produces dermal reactions greater than
those from unpolluted areas [111]. Cakmak et al. [117]
reported the relationship between air pollution and
the risk of hospitalization for asthma with pollens and
fungal spores endorsing this situation. Guilbert et  al.
13
84
Fig. 3  The interrelation between
Airway remodeling Airway responsiveness
the various components of genes
the binomial air pollutants in
asthma (Guarnieri et al. [28])
[118] confirmed the association of exposure to ­PM10 and
aeroallergens with hospitalizations for asthma.
Human airway epithelium seems to play an important role
in the initiation and control of the innate immune responses to
different types of environmental factors contributors to asthma
pathogenesis, such as allergens, microbes, or pollutants [119].
It is accepted that epigenetic mechanisms play a pivotal
role in the regulation of different cell populations leading
T and B cells to participate in the pathogenesis of asthma.
The effects of environmental factors on the development of
asthma are mediated, at least in part, by DNA methylation
and histone modifications [119].
The common feature of such mechanisms is that they
induce asthma without affecting the nucleotide sequence of
the genomic DNA, in accordance with the classic definition
of epigenetic mechanisms [120].
Thus, through these various routes, exposure to pollutants
increases asthma outcomes in all recognized asthma
subtypes.
In summary, air pollutants might cause oxidative injury
to the airways that leads to inflammation and remodeling,
which, in a genetically predisposed individual, could result
in clinical asthma. One predisposing factor might be atopy,
and air pollutants could increase the risk of sensitization and
the responses to inhaled allergens in individuals with asthma.
Conclusions
Exposure to pollutants in inspired air is one of the many
clinical points to investigate during a medical interview
for the diagnosis of asthma. It must be considered in each
13
Clinical Reviews in Allergy & Immunology (2022) 62:72–89
Antioxidant Immune response
genes genes genes
Air pollutants
Oxidative stress Th2 phenotype
Allergen Air
pollution
Injury and inflammation Sensitisation
Asthma
Air pollution
Exacerbations
individual case, even knowing that there is rarely only a
single cause. This interference or causality can occur in
allergic or non-allergic asthma, confirming the concept of
asthma as a multifactorial disease.
Air pollution plays a significant role in asthma morbidity
and mortality rates. The impact is increasing while many
countries have not taken effective actions to reduce
emissions of these toxic agents.
One of the relevant impacts of air pollution is the
association with the increased incidence, prevalence,
and exacerbation of asthma, as shown in this narrative
review. Exposure to industrial pollution and traffic-related
pollutants is an important risk factor for the main outcomes
in childhood asthma. However, in adults, the conclusions are
less definitive, but additional studies are gradually clarifying
our understanding in this point.
The mechanisms through which pollutants induce asthma
and other respiratory diseases are multiple, but the key
seems to be the inflammatory cascade. There is evidence
that epigenetic changes occurring in the respiratory tract
microbiome play a role in the pathophysiology of these
clinical conditions.
The advance in science on the harmful effects of
pollution on respiratory diseases, especially asthma,
has not yet experienced the necessary diffusion, even
among professionals in the various health professions.
However, certainly, new and important advances will lead
us to disseminate information about the importance of
environmental pollution for all humankind.
Funding  The authors claim that they have not received any form of
funding related to this article.
Clinical Reviews in Allergy & Immunology (2022) 62:72–89
Compliance with Ethical Standards  Am Thorac Soc 16(10):1207–1214. https​://doi.org/10.1513/
Conflict of Interest  The authors declare that they have no conflict of
interest.
Research involving Human Participants and/or Animals  This paper did
not involve human participants or animals.
Informed Consent  As this review did not include any human or animal
participants, there was no need of informed consent.
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